Stem cell therapy and Ab clearance through neprilysin (NEP) gene delivery have recently been shown to be effective treatments on mouse Alzheimer's Disease (AD) models. It is still unknown whether their effects are additive. We propose here to test this question by the transplantation of an embryonic stem cell (ESC) line that has been modified to express NEP under the control of a doxycycline-inducible promoter. Through this combined strategy of gene and cell therapy, it is expected that the impaired neural circuit may be repaired by the formation of synapses between the engrafted and host neurons. It is also expected that the engrafted cells may secrete neurotrophic factors and achieve local environment enrichment to improve neuronal survival. Moreover, the engrafted cells may be induced to overexpress NEP to degrade A and reduce plaque burden. Therefore, the proposed study may lead to a more effective treatment option for AD. The innovation of the proposed strategy lies not only in the potential of combined benefit from gene and cell therapy, but also in its ability to allow external control of the biochemical activity of engrafted cells. By transplantng the proposed genetically modified cells, we will test whether NEP expression after cell graft can be controlled by an orally administrated drug, and how this affects brain A levels and disease progress. The ability to control the activity of engrafted cells is of paramount importance to future clinical applications as it can help to achieve optimal therapeutic results and, more importantly, avoid possible adverse effects caused by the over-supply of therapeutic cells. Although AD is studied in the current proposal, we envision that the proposed concept and technology can be readily modified to deliver other therapeutic cells and genes for a wide range of neurological disorders. PUBLIC HEALTH RELEVANCE: This project aims to test the effect of a combined cell gene therapy strategy on Alzheimer's Disease (AD). The strategy combines the advantages of stem cell therapy and A clearance, and may represent a more efficient treatment option for AD. We will also test a strategy of using oral drugs to control the therapeutic gene, so that possible adverse effects can be avoided.